The use of a designed viral vector that can destroy cancer cells while leaving normal cells largely unharmed. The virus also stimulates an immunological response by producing a special factor (GM-CSF) to attract and promote the development of dendritic and T effector cells. It forms the hypothesis that this regimen may be used for people who have failed current forms of treatment and are recommended for cystectomy. It is with hope that this novel therapy will be able to delay or potentially avoid cystectomy for this patient population. Bladder instillation of this agent causes little long lasting side effects and may drastically improve the stimulation of the immune system for local cancer cell death as well as destroying those tumor cells that may have travelled to regional lymph nodes or distant organs.

An Integrated Phase II/III, Open Label, Randomized and Controlled Study of the Safety and Efficacy of CG0070 Adenovirus Vector Expressing GM-CSF in Patients With Non-Muscle Invasive Bladder Cancer With Carcinoma In Situ Disease Who Have Failed BCG

'CR' Proportion is confirmed by negative biopsy, cystoscopy, cytology weekly times 2 with the first assessment three months after first intravesical treatment and then assessed again at 9 month. Two consectutive positive urine cytologies to confirm a persistent or recurrent disease if visual and biopsy is negative. Random biopsy mandatory at the first assessment in the trigone, bladder dome, right, left , anterior and posterior of the bladder wall.

DCR proportion of DCR lasting 12 months or longer will be conducted after a follow up period of 15 months for each patient. The first complete response assessment will be at 3 month.

Secondary Outcome Measures:

Progression rate to muscle invasive disease [ Time Frame: Throughout the study with expected average of 12 months ] [ Designated as safety issue: No ]

The Progression rate to muscle invasive disease rate is based on analysis from comparing disease status at the time of enrollment versus disease status (for those patients with muscle invasion) at the time of cystectomy or TURBT

CG0070 adenoviral vector with GM-CSF expression given intravesically 1x10e12 viral particles for each instillations, weekly times six

Other Names:

oncolytic virus

CG0070

GM-CSF expression

adenoviral vector

Active Comparator: Chemotherapy or Interferon

Quadruple Choice as interventions

Mitomycin C

Interferon

Valrubicin

Gemcitabine

Other: Control Arm: Quadruple Choice

Quadruple Choice Treatment Options:

I. Mitomycin C II. Interferon III. Valrubicin IV. Gemcitabine

Other Names:

Mitomycin C

Interferon

Valrubicin

Gemcitabine

Detailed Description:

After the phase I/II CG0070 trial review, it became apparent that the use of CG0070 oncolytic vaccine as an intravesical agent for oncolytic lysis of tumor cells, together with the transcription of GM-CSF on site, may have distinct advantages. This first study showed excellent tumor response rates of 48-77% depending on the dose schedule administered. All of these patients had residual non-muscle invasive bladder cancer who have previously failed BCG therapy at the time of treatment.

With the addition of a transduction agent such as DDM, the intravesical instillation of CG0070 enabled uniform distribution of viral particles and exposure to the tumor during those 30-60 minutes instillations as contrast to the intra-tumor injection, intra-arterial or intravenous injection of viral particles in other oncolytic viral trials. Some or most of these delivering methodologies have obvious intrinsic imperfections and potential toxicity. This unique opportunity of an relatively easy intravesical tumor exposure is difficult to duplicate in other solid tumor models.

The replication of CG0070 in the majority of patients during the first phase I/II trial indicated tumor lysis with release of tumor specific or tumor associated antigens that have been stably expressed, in abundant quantities during tumor cell death. Release of tumor antigens have been the key elements, together with sufficient on-site GM-CSF, in stimulating strong cross-presentation and confirmation signals to the antigen presenting cells such as dendritic cells interacting with CD4+ and CD8+ T cells. This concept of a "real time" vaccine like regimen is expected to compare favorably with other forms of cancer immunotherapy treatment such as BCG in this patient population.

It is with this thought that CG0070 may find a success in this setting because of a reasonably and proven complete response rate in residual and failed BCG bladder cancer patients in the first phase I/II study (some cases with only one instillation). Of importance as well, is the demonstration in the study data of a strong GM-CSF expression during its replication phase. Those patients with carcinoma in situ disease and those with RB pathway dysfunction were particularly responsive.

It is therefore, desirable to formulate a protocol to encompass the specialty of this oncolytic vaccine and the unique intravesical delivery to prove the efficacy by a randomized controlled study. This opportunity allows a study on the CG0070's beneficial effects, if any, on the standard of care for carcinoma in situ non muscle invasive bladder cancer patients after they failed BCG therapy. The prognosis of this group presently depends mainly on early radical cystectomy, which carries a high morbidity and decrease of quality of life generally viewed as unacceptable for this group of older patients.

Eligibility

Ages Eligible for Study:

18 Years and older

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must be considered high risk, with pathologically confirmed high grade disease (HG) WHO 2004

Patients must have pathologically-proven unresectable, primary, secondary or concurrent carcinoma in situ disease, defined by having either Ta and/or T1 with CIS, or CIS

Patients must have no evidence of muscle invasive disease

Patient need to sign a specific informed consent acknowledging that a delay of cystectomy may lead to an increase chance of progression and/or metastasis with serious or sometimes fatal consequences.

Patients must have received at least two or more prior courses of intravesical therapy. BCG must have been one of the prior therapies administered. Patients can have either failed BCG induction therapy within a six month period or have been successfully treated with BCG, but subsequently found to have recurrence. The standard course of intravesical therapy must include six weekly treatments (allowable range of instillations per course is 4-9). The second course of BCG can consist of three weekly treatments

Patients must be able to enter into the study within five weeks of their most recent diagnostic procedure, which is usually a diagnostic biopsy, a transurethral resection of bladder tumor (TURBT) procedure or other diagnostic scanning such as CT and PET procedures.

Patient to provide a tumor specimen for determination of RB pathway status

Exclusion Criteria:

Previous systemic chemotherapy or radiation for bladder cancer. Note: Prior immunotherapy or intravesical (administered within the bladder) chemotherapy for superficial disease is acceptable

No bladder cancer residual disease, such as patients that are rendered disease free by TURBT

History of anaphylactic reaction following exposure to humanized or human therapeutic monoclonal antibodies, hypersensitivity to GM-CSF or yeast derived products, clinically meaningful allergic reactions or any known hypersensitivity or prior reaction to any of the formulation excipients in the study drugs.

Known infection with HIV, HBV or HCV.

Anticipated use of chemotherapy, radiotherapy, or other immunotherapy not specified in the study protocol while on study

Any underlying medical condition that, in the Investigator's opinion, will make the administration of study vaccine hazardous to the patient, would obscure the interpretation of adverse events, or surgical resection. Anticipated use of chemotherapy, radiotherapy, or other immunotherapy not specified in the study protocol while on study

Systemic treatment on any investigational clinical trial within 28 days prior to registration.

Concurrent treatment with immunosuppressive or immunomodulatory agents, including any systemic steroid (exception: inhaled or topically applied steroids, and acute and chronic standard dose NSAIDs, are permitted). Use of a short course (i.e., ≤ 1 day) of a glucocorticoid is acceptable to prevent a reaction to the IV contrast used for CT scans.

History of partial cystectomy in the setting of bladder cancer primary tumor.

History of anaphylactic reaction following exposure to humanized or human therapeutic monoclonal antibodies, hypersensitivity to GM-CSF or yeast derived products, clinically meaningful allergic reactions or any known hypersensitivity or prior reaction to any of the formulation excipients in the study drugs.

History of stage III or greater cancer, excluding urothelial cancer. Basal or squamous cell skin cancers must have been adequately treated and the subject must be disease-free at the time of registration. Subjects with a history of stage I or II cancer, must have been adequately treated and have been disease-free for ≥ 3 years at the time of registration.

All infections must be resolved and the patient must remain afebrile for seven days without antibiotics prior to being placed on study

Any underlying medical condition that, in the Investigator's opinion, will make the administration of study vaccine hazardous to the patient, would obscure the interpretation of adverse events, or not permit adequate surgical resection.

Unwilling or unable to comply with the protocol or cooperate fully with the investigator and site personnel

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01438112